DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The present Application, filed March 1, 2023, is a national stage entry under 35 U.S.C. § 371 of International Patent Application No. PCT/US2021/049094, filed September 3, 2021, which claims priority to U.S. Provisional Patent Application No. 63/074,905, filed September 4, 2020.
Status of the Claims
In the amendment filed June 22, 2023, claims 3-9, 11-15, 17-21, 23, 25, 27-29, 32-35, 37-54, 56-59, 61-67, 69-73, 75-80, 82-89, 91-92, 94-99, and 103-105 are canceled. Claims 10, 16, 22, 24, 26, 30-31, 36, 55, 60, 68, 74, 81, 90, 93, and 100-102 are amended. Claims 1-2, 10, 16, 22, 24, 26, 30-31, 36, 55, 60, 68, 74, 81, 90, 93, and 100-102 are currently pending.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on June 1, 2023 and May 8, 2024 are acknowledged.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. § 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. § 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-2, 10, 16, 22, 24, 26, 30-31, 36, 55, 60, 68, 74, 81, 90, and 100-102 are indefinite:
Claims 1-2, 10, 16, 22, 24, 26, 30-31, 36, 55, 60, 68, 74, 81, 90, and 100-102 are rejected under 35 U.S.C. § 112(b) or 35 U.S.C. § 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 is indefinite for reciting a variety of “substituted or unsubstituted” moieties for each of variable groups R1, R2, R4-R11, and RB. For example, R1 is recited as being “substituted or unsubstituted phenyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted naphthyl, or substituted or unsubstituted mono- or bi-cyclic heteroaryl.” Paragraph [0075] of the specification, which defines the general use of the word “substituted” as including, but not being limited to, dozens of possible functional groups appended to the base group. Paragraph [0075] further notes that the term “substituted” can encompass such substituents being further substituted with additional such substituents. While not expressly affirmed or denied, it could be inferred that these secondary substituents can further be substituted, and so forth, ad infinitum. Even without this, the recited pattern of substitutions of virtually unlimited number and scope, results in a genus of structures of virtually unlimited structure and size, where the required core can easily be dwarfed by the variety and number of unspecified substituents. Such a vast genus, structurally largely undefined, is by its nature indefinite.
Claims 2, 10, 16, 22, 24, 26, 30-31, 36, 55, 60, 68, 74, 81, 90, and 100-102 are indefinite for depending from claim 1 without curing this indefiniteness.
Claims 1-2, 10, and 16 are further indefinite for reciting that various moieties can be “a carboxylic acid isostere,” because one of ordinary skill in the art could not reasonably determine the metes and bounds of this limitation. Paragraph [0562] states that such a “carboxylic acid isostere” refers to a functional group or moiety that exhibits similar physical, biological and/or chemical properties to those of a carboxylic acid moiety. However, in the absence of any guideposts for similarity, this is purely qualitative and would not enable one to determine with certainty which moieties are sufficiently similar, physically, biologically, and/or structurally. The same paragraph further lists several dozen examples, noting that the list is not limiting. Notably, the list includes routine examples, such as tetrazoles, as well as niche examples, such as cyclopentane-1,3-diones. Notably, the listed examples do not appear to have an overarching structural or chemical motif. For this reason, and because the examples are expressly non-limiting, they would not enable one to reasonably determine the metes and bounds of the intended category of “carboxylic acid isosteres.” For this reason, claims 1-2, 10, and 16 are further indefinite, and their dependent claims are likewise indefinite for failing to cure this indefinite of their base claim(s).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. § 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. § 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim 1 is obvious over Eiring:
Claims 1 is rejected under 35 U.S.C. § 103 as being unpatentable over the non-patent publication, Combined STAT3 and BCR-ABL1 inhibition induces synthetic lethality in therapy-resistant chronic myeloid leukemia, Leukemia, 29, pgs. 586-597 (2015) by Eiring et al. (hereinafter, “Eiring”).
Claim 1 recites a compound of Formula (A) or a salt or solvate thereof:
PNG
media_image1.png
254
265
media_image1.png
Greyscale
where the variable substituents are as defined. Of note, R3 is
PNG
media_image2.png
105
120
media_image2.png
Greyscale
where each substituent is independently H, F, Cl, Br, or I, with the further limitations that at least four are not H (i.e. at least four are halo) and at least one is not F.
Eiring teaches the development of novel STAT3 inhibitors in the pursuit of dual STAT3/Tyrosine kinase inhibition (Abstract). Eiring teaches the synthesis and testing of a series of STAT3 inhibitors designed by varying the previously-known inhibitor SF-1-066 (pg. 590, left column, first full paragraph). Eiring discloses a series of variants (e.g. Figure 3a) such as compounds 2a, 9l, and 9n.
PNG
media_image3.png
302
667
media_image3.png
Greyscale
Each of these compounds is nearly a compound of instant claim 1 where n is one and R7 and R8 are H; R1 is cycloalkyl-substituted phenyl; R4 is carboxylic acid (C(O)OR11 where R11 is H); m is one and RB is hydroxyl (-OR11 where R11 is H); p is one and R5 and R6 are H; X is O; q is one with R9 and R10 are H; and instant R2 is perfluorophenyl (substituted phenyl). Each compound differs from the compounds of instant formula (A) only in the R3 position. In the case of Compound 2a, the perfluorophenyl group is nearly a substituted phenyl R3 as required by instant formula (A), but does not satisfy the exclusionary requirement that at least one substituent on the phenyl must be H, B, Cl, or I (at least one substituent can’t be F). The R3 phenyl groups on Compounds 9l and 9n do not satisfy the requirement that at least four substituents must halo, as each of these has only one halo substituent (Cl in the case of Compound 9l and F in the case of Compound 9n).
PNG
media_image4.png
192
590
media_image4.png
Greyscale
Viewing these compounds together, and notwithstanding that Compound 2a has a somewhat lower EC50 than do Compounds 9l and 9n, it would have been clear that fluorine is not required at all positions on the phenyl ring of instant group R3 for an effective STAT3 inhibitor. Furthermore, one would have been motivated to try different combinations, such as substituting one or more of the fluorines on instant group R3 of Compound 2a, with hydrogen and/or with other halogen substituents, and would have had a reasonable expectation of success in obtaining an effective STAT3 inhibitor through such modifications.
Claims 100-102 are obvious over Eiring and Huang:
Claims 1 is rejected under 35 U.S.C. § 103 as being unpatentable over Eiring, in view of U.S. Patent Application Publication No. 2002/0151504 to Huang et al. (hereinafter, “Huang”).
Claim 100 recites a pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient or carrier. Eiring is applied to instant claim 100 as to claim 1, above, but does not expressly encompass a pharmaceutical composition having the disclosed compound along with a carrier or excipient. It would have been obvious to incorporate the compounds disclosed in Eiring into a pharmaceutical composition along with an excipient or carrier, because such compositions of STAT inhibitors, like the compounds of Eiring, were well-known in the art. See, for example Huang.
Huang teaches compounds and methods for the inhibition of STAT transcription factors (Abstract). Huang teaches pharmaceutical compositions having such compounds, in combination with a pharmaceutically acceptable excipient. It would have been obvious to combine a compound of Eiring (a STAT inhibitor) with an excipient for prepare a pharmaceutical composition, as taught by Huang.
Claims 101 and 102 are directed to methods for treating disease, including various cancers, involving administering a compound of instant claim 1. Eiring is applied to claims 101-102 as to claim 1, above, but does not expressly disclose such a method. It would have been obvious to utilize the compounds of Eiring in this fashion because such uses of STAT inhibitors were well-known in the art, as exemplified by Huang. Huang teaches, for example, methods of modulating STAT-dependent disorders comprising administering a STAT-modulating (inhibiting) compound (claim 65), and teaches that such disorders can include cancers (paragraph [0022]). It thus would have been obvious to apply the compounds of Eiring to such a method as taught by Huang.
Claims 1-2, 10, 16, 26, 31, 36, 60, 68, 74, 81, 90, and 101-102 are obvious over Gunning:
Claims 1-2, 10, 16, 22, 24, 26, 30-31, 36, 55, 60, 68, 74, 81, 90, and 100-102 are rejected under 35 U.S.C. § 103 as being unpatentable over U.S. Patent Application Publication No. 2017/0101369 to Gunning et al. (hereinafter, “Gunning”).
Gunning teaches inhibitors of STAT5 of the Formula
PNG
media_image5.png
103
124
media_image5.png
Greyscale
(Abstract) where the variables are as defined, and create a genus that overlaps with that of instant claim 1. For example, a compound such as
PNG
media_image6.png
414
466
media_image6.png
Greyscale
would be a compound of instant claims 1 and 2 where (in instant Formula (I) – claim 2 – terms), R1 is alkyl substituted phenyl; n, p, and q are one and R5-R10 are H; R4 is carboxyl, RB and RB1 are methoxy (-OR11), and m is three; X is O and R3 is o-bromo-tetrafluorophenyl; and R2 is pentafluorophenyl. This is also a compound of the formula of Gunning, where R1 is -CH2-(C6)-aryl, with alkyl substitution on the aryl; X is p-carboxyl and R is (C1)-alkoxy; also compound of the formula of claim 1 of Gunning, where R4 and R5 are collectively carbonyl; n is one; R2 is pentafluorophenyl; and R3 is o-bromo-tetrafluorophenyl. Because the compounds of instant claims 1-2 have a highly similar core structure and function, and the structural genera recited in instant claims 1 and 2 have actual overlap with the structural genus disclosed in Gunning, claims 1-2 are obvious over Gunning.
With respect to claims 10, 16, 26, 31, 36, 60, 68, 74, 81, and 90, each of these depends from claim 2 and further narrows the genus of compound of claim 2, but remains in overlap with the genus of compounds of Gunning. For example, the exemplary compound shown above has instant R3 that is one of the alternatives recited in claim 90. As such, each of these claims is obvious over Gunning for the same rationale applied to claims 1-2, above.
With respect to claim 100, Gunning teaches pharmaceutical compositions having the disclosed compounds in combination with pharmaceutically acceptable excipients or carriers (e.g. paragraph [0015]). With respect to claims 101-102, are obvious variants of claims 18-21 of Gunning, discloses methods for treating diseases, such as cancer, that are mediated by STAT5 proteins (e.g. STAT5a and b – see paragraphs [0092]-[0093] and [0003]), comprising administering a disclosed STAT5 inhibitor. It thus would have been obvious to utilize the similar, and generically overlapping, compounds of instant claim 1 in a comparable method directed to modulating STAT5 activity in a subject having a condition such as cancer.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 10, 16, 26, 31, 36, 60, 68, 74, 81, 90, and 101-102 are rejected for nonstatutory double patenting over the ’107 patent:
Claims 1-2, 10, 16, 22, 24, 26, 30-31, 36, 55, 60, 68, 74, 81, 90, and 100-102 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 and 18-21 of U.S. Patent No. 10,519,107 (hereinafter, “the ’107 patent”). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ’107 patent recite a genus of compounds that substantially overlaps with the genus of compounds of instant claim 1 and its dependent claims.
Claim 1 of the ’107 patent recites a compound of the Formula
PNG
media_image5.png
103
124
media_image5.png
Greyscale
where the variables are as defined, and create a genus that overlaps with that of instant claim 1. For example, a compound such as
PNG
media_image6.png
414
466
media_image6.png
Greyscale
would be a compound of instant formulae (A) and (I), where (in instant Formula (I) terms), R1 is alkyl substituted phenyl; n, p, and q are one and R5-R10 are H; R4 is carboxyl, RB and RB1 are methoxy (-OR11), and m is three; X is O and R3 is o-bromo-tetrafluorophenyl; and R2 is pentafluorophenyl. This is also a compound of the Formula of claim 1 of the ’107 patent, where R1 is -CH2-(C6)-aryl, with alkyl substitution on the aryl; X is p-carboxyl and R is (C1)-alkoxy; also compound of the formula of claim 1 of the ’107 patent, where R4 and R5 are collectively carbonyl; n is one; R2 is pentafluorophenyl; and R3 is o-bromo-tetrafluorophenyl. Instant method claims 101-102 are obvious variants of claims 18-21 of the ’107 patent, directed to methods for treating disease, including various cancers.
Claim 100 is rejected for nonstatutory double patenting over the ’107 patent and Huang:
Claim 100 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 and 18-21 of the ’107 patent, in view of Huang. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ’107 patent recite a genus of compounds that, in combination with the teachings of Huang, substantially overlaps with the pharmaceutical compositions of instant claim 100.
Claim 100 recites a pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient or carrier. The claims of the ’107 patent are applied to instant claim 100 as to claim 1, above, but do not expressly encompass a pharmaceutical composition having the recited compound along with a carrier or excipient. It would have been obvious to incorporate the compounds claimed in the ’107 patent into a pharmaceutical composition along with an excipient or carrier, because such compositions of STAT inhibitors, like the compounds of the ’107 patent, were well-known in the art. See, for example Huang.
Huang teaches compounds and methods for the inhibition of STAT transcription factors (Abstract). Huang teaches pharmaceutical compositions having such compounds, in combination with a pharmaceutically acceptable excipient. It would have been obvious to combine a compound of the ’107 patent (a STAT inhibitor) with an excipient for prepare a pharmaceutical composition, as taught by Huang.
Claims 1 and 100-102 are rejected for nonstatutory double patenting over the ’707 patent:
Claims 1 and 100-102 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No. 8,846,707 (hereinafter, “the ’707 patent”). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ’707 patent recite a genus of compounds that substantially overlaps with the genus of compounds of instant claim 1 and its dependent claims.
Claim 1 of the ’707 patent recites a compound having a structure represented by a formula:
PNG
media_image7.png
112
124
media_image7.png
Greyscale
where the variable groups are as defined. For example, R1 can be aryl (e.g. phenyl); m can be zero; and R2 and R3 can each be aryl substituted with 0-5 substituents such as halo. Such a compound would be a compound of instant formula (A). With respect to instant claim 100, claim 4 of the ’707 patent recites an analogous pharmaceutical composition. With respect to instant claims 101-102, these are obvious variants of claims 5-6 of the ’707 patent, directed to methods for treating disease, including various cancers.
Claims 1 and 100 are rejected for nonstatutory double patenting over the ’373 patent:
Claims 1 and 100 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 and 18-21 of U.S. Patent No. 10,196,373 (hereinafter, “the ’373 patent”). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ’373 patent recite a genus of compounds that substantially overlaps with the genus of compounds of instant claim 1 and its dependent claims.
PNG
media_image8.png
133
213
media_image8.png
Greyscale
where the variable groups are as defined. For example, m can be zero; and R2 and R3 can each be aryl substituted with 0-5 substituents such as halo. Such a compound would be a compound of instant formula (A). With respect to instant claim 100, claim 4 of the ’373 patent recites an analogous pharmaceutical composition. With respect to instant claims 101-102, these are obvious variants of claims 5-6 of the ’373 patent, directed to methods for treating disease, including various cancers.
Claims 1 and 100 are rejected for nonstatutory double patenting over the ’373 patent and Huang:
Claims 1 and 100 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of the ’373 patent, in view of Huang. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ’373 patent recite a genus of compounds that, in combination with the teachings of Huang, substantially overlaps with the methods of instant claims 101-102.
Claims 101 and 102 are directed to methods for treating disease, including various cancers, involving administering a compound of instant claim 1. The claims of the ’373 patent do not directly recite such a method, but it would have been obvious to utilize the compounds of the ’373 patent in this fashion because such uses of STAT inhibitors were well-known in the art, as exemplified by Huang. Huang teaches, for example, methods of modulating STAT-dependent disorders comprising administering a STAT-modulating (inhibiting) compound (claim 65), and teaches that such disorders can include cancers (paragraph [0022]). It thus would have been obvious to apply the compounds of the ’373 patent to such a method as taught by Huang.
Allowable Subject Matter
Claim 93 is allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDER K SHOWALTER whose telephone number is (571)270-0610. The examiner can normally be reached M-F 9:00 am to 5:00 pm, eastern time.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S Lundgren can be reached on (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ALEXANDER K. SHOWALTER/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629